Isoquinolinone potassium channel inhibitors

ABSTRACT

The present invention relates to compounds having the structure (I) useful as potassium channel inhibitors to treat cardiac arrhythmias, and the like.

CROSS REFERENCE TO RELATED APPLICATION

This application is a U.S. National Phase application under 35 U.S.C.371 of PCT Application No. PCT/US2004/030431, filed Sep. 17, 2004, whichclaims priority under 35U.S.C. 119(e) from U.S. Provisional ApplicationSer. No. 60/505,101, filed Sep. 23, 2003.

BACKGROUND OF THE INVENTION

The present invention relates broadly to compounds that are useful aspotassium channel inhibitors. Compounds in this class may be useful asKv1.5 antagonists for treating and preventing cardiac arrhythmias, andthe like.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmiain clinical practice and is likely to increase in prevalence with theaging of the population. While AF is rarely fatal, it can impair cardiacfunction and lead to complications such as the development of congestiveheart failure, thromboembolism, or ventricular fibrillation.

Currently available antiarrhythmic agents have been developed for thetreatment of ventricular and atrial/supraventricular arrhythmias.Malignant ventricular arrhythmias are immediately life-threatening andrequire emergency care. Drug therapy for ventricular arrhythmia includesClass Ia (eg. procainamide, quinidine), Class Ic (eg. flecainide,propafenone), and Class III (amiodarone) agents, which pose significantrisks of proarrhythmia. These Class I and III drugs have been shown toconvert AF to sinus rhythm and to prevent recurrence of AF (Mounsey, JP, DiMarco, J P, Circulation, 102:2665-2670), but pose an unacceptablerisk of potentially lethal ventricular proarrhythmia and thus mayincrease mortality (Pratt, C M, Moye, L A, Am J. Cardiol., 65:20B-29B,1990; Waldo et al, Lancet, 348:7-12, 1996; Torp-Pedersen et al, ExpertOpin. Invest. Drugs, 9:2695-2704, 2000). These observations demonstratea clear unmet medical need to develop safer and more efficacious drugsfor the treatment of atrial arrhythmias. Class III antiarrhythmic agentscause a selective prolongation of the APD without significant depressionof cardiac conduction or contractile function. The only selective ClassIII drug approved for clinical use in atrial fibrillation is dofetilide,which mediates its anti-arrhythmic effects by blocking I_(Kr), therapidly activating component of I_(K) found in both atrium and ventriclein humans (Mounsey, J P, DiMarco, J P, Circulation, 102:2665-2670).Since I_(Kr) blockers increase APD and refractoriness both in atria andventricle without affecting conduction per se, theoretically theyrepresent potentially useful agents for the treatment of arrhythmiaslike AF (Torp-Pedersen, et al, Expert Opin. Invest. Drugs, 9:2695-2704,2000). However, these agents have the major liability of an enhancedrisk of proarrhythmia at slow heart rates.

The ultrarapid delayed rectifier K⁺ current, I_(Kur), has been observedspecifically in human atrium and not in ventricle. The molecularcorrelate of I_(Kur) in the human atrium is the potassium channeldesignated Kv1.5. I_(Kur) is believed to contribute significantly torepolarization in human atrium. Consequently, a specific blocker ofI_(Kur), that is a compound which blocks Kv1.5, would overcome theshortcoming of other compounds by prolonging refractoriness throughretardation of the repolarization in the human atrium without causingthe delays in ventricular repolarization that underlie arrhythmogenicafter depolarizations and acquired long QT syndrome observed duringtreatment with current Class III drugs. Kv1.5 blockers exhibiting theseproperties have been described (Peukert et al, J. Med. Chem.,46:486-498, 2003; Knobloch et al, Naunyn-Schmedieberg's Arch. Pharmacol.366:482-287, 2002; Merck & Co., Inc. WO0224655, 2002).

The compounds described in this invention represent a novel structuralclass of Kv1.5 antagonist.

SUMMARY OF THE INVENTION

This invention relates to potassium channel inhibitors of generalstructural Formula I

The compounds of this invention are useful in the treatment andprevention of cardiac arrhythmias, and the like. Also within the scopeof this invention are pharmaceutical formulations comprising a compoundof Formula I and a pharmaceutical carrier.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present invention is a compound of formula I

or a pharmaceutically acceptable salt, crystal form, or hydrate,wherein:A is

-   -   a) an aryl ring, wherein any stable aryl ring atom is        independently unsubstituted or substituted with        -   1) halogen,        -   2) NO₂,        -   3) CN,        -   4) CR⁴⁶═C(R⁴⁷R⁴⁸)₂,        -   5) C≡CR⁴⁶,        -   6) (CR^(i)R^(j))_(r)OR⁴⁶,        -   7) (CR^(i)R^(j))_(r)N(R⁴⁶R⁴⁷),        -   8) (CR^(i)R^(j))_(r)C(O)R⁴⁶,        -   9) (CR^(i)R^(j))_(r)C(O)OR⁴⁶,        -   10) (CR^(i)R^(j))_(r)R⁴⁶,        -   11) (CR^(i)R^(j))_(r)S(O)₀₋₂R⁶¹,        -   12) (CR^(i)R^(j))_(r)S(O)₀₋₂N(R⁴⁶R⁴⁷),        -   13) OS(O)₀₋₂R⁶¹,        -   14) N(R⁴⁶)C(O)R⁴⁷,        -   15) N(R⁴⁶)S(O)₀₋₂R⁶¹,        -   16) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹,        -   17) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹OR⁴⁷,        -   18) (CR^(i)R^(j))_(r)N(R⁴⁶) (CR^(k)R^(l))_(s)C(O)N(R⁴⁷R⁴⁸),        -   19) N(R⁴⁶) (CR^(i)R^(j))_(r)R⁶¹,        -   20) N(R⁴⁶) (CR^(i)R^(j))_(r)N(R⁴⁷R⁴⁸),        -   21) (CR^(i)R^(j))_(r)C(O)N(R⁴⁷R⁴⁸), or        -   22) oxo, or    -   b) a heteroaryl ring selected from the group consisting of        -   a 5-membered unsaturated monocyclic ring with 1, 2, 3 or 4            heteroatom ring atoms selected from the group consisting or            N, O or S,        -   a 6-membered unsaturated monocyclic ring with 1, 2, 3 or 4            heteroatom ring atoms selected from the group consisting N,            O and S, and        -   a 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3            or 4 heteroatom ring atoms selected from the group            consisting or N, O or S;        -   wherein any stable S heteroaryl ring atom is unsubstituted            or mono- or di-substituted with oxo, and any stable C or N            heteroaryl ring atom is independently unsubstituted or            substituted with            -   1) halogen,            -   2) NO₂,            -   3) CN,            -   4) CR⁴⁶═C(R⁴⁷R⁴⁸)₂,            -   5) C≡CR⁴⁶,            -   6) (CR^(i)R^(j))_(r)OR⁴⁶,            -   7) (CR^(i)R^(j))_(r)N(R⁴⁶R⁴⁷),            -   8) (CR^(i)R^(j))_(r)C(O)R⁴⁶,            -   9) (CR^(i)R^(j))_(r)C(O)OR⁴⁶,            -   10) (CR^(i)R^(j))_(r)R⁴⁶,            -   11) (CR^(i)R^(j))_(r)S(O)₀₋₂R⁶¹,            -   12) (CR^(i)R^(j))_(r)S(O)₀₋₂N(R⁴⁶R⁴⁷),            -   13) OS(O)₀₋₂R⁶¹,            -   14) N(R⁴⁶)C(O)R⁴⁷,            -   15) N(R⁴⁶)S(O)₀₋₂R⁶¹,            -   16) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹,            -   17) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹OR⁴⁷,            -   18) (CR^(i)R^(j))_(r)N(R⁴⁶)                (CR^(k)R^(l))_(s)C(O)N(R⁴⁷R⁴⁸),            -   19) N(R⁴⁶) (CR^(i)R^(j))_(r)R⁶¹,            -   20) N(R⁴⁶) (CR^(i)R^(j))_(r)N(R⁴⁷R⁴⁸),            -   21) (CR^(i)R^(j))_(r)C(O)N(R⁴⁷R⁴⁸), or            -   22) oxo;                R¹ is selected from the group consisting of    -   1) hydrogen,    -   2) (CR^(a)R^(b))_(n)R⁴⁰,    -   3) (CR^(a)R^(b))_(n)OR⁴⁰,    -   4) (CR^(a)R^(b))_(n)N(R⁴⁰R⁴¹),    -   5) (CR^(a)R^(b))_(n)N(R⁴⁰)C(O)OR⁴¹,    -   6) (CR^(a)R^(b))_(n)N(R⁴⁰) (CR^(c)R^(d))₂N(R⁴¹)C(O)R⁴⁹,    -   7) C₃₋₈ cycloalkyl,    -   8) (CR^(a)R^(b))_(n)C(O)OR⁴⁰,    -   9) (CR^(a)R^(b))_(n)N(R⁴⁰) (CR^(c)R^(d))₁₋₃R⁴¹,    -   10) (CR^(a)R^(b))_(n)S(O)₀₋₂R⁶,    -   11) (CR^(a)R^(b))_(n)S(O)₀₋₂N(R⁴⁰R⁴¹),    -   12) (CR^(a)R^(b))_(n)N(R⁴⁰)R⁶OR⁴¹,    -   13) (CR^(a)R^(b))_(n)N(R⁴⁰) (CR^(c)R^(d))₀₋₆C(O)N(R⁴¹R⁴²);        R⁵ is selected from the group consisting of    -   1) hydrogen,    -   2) halogen,    -   3) S(O)₀₋₂N(R⁵³R⁵⁰),    -   4) S(O)₀₋₂R⁶²,    -   5) CH₃,    -   6) C₃-C₆ alkyl,    -   7) C₃-C₁₀ cycloalkyl,    -   8) R⁸²,    -   said alkyl, and cycloalkyl is unsubstituted, mono-substituted        with R²², di-substituted with R²² and R²³, tri-substituted with        R²², R²³ and R²⁴, or tetra-substituted with R²², R²³, R²⁴ and        R²⁵;        or R¹ and R⁵ together with the atoms to which they are attached,        form a ring selected from the group of structures consisting of

-   -   where u is 0 or 1, R⁹⁹ is hydrogen or —OH, and X is O or        =NOH;        R², R⁸, R⁹ and R¹⁰ are independently selected from:    -   1) hydrogen,    -   2) halogen,    -   3) NO₂,    -   4) CN,    -   5) CR⁴³═C(R⁴⁴R⁴⁵),    -   6) C≡CR⁴³,    -   7) (CR^(e)R^(f))_(p)OR⁴³,    -   8) (CR^(e)R^(f))_(p)N(R⁴³R⁴⁴),    -   9) (CR^(e)R^(f))_(p)C(O)R⁴³,    -   10) (CR^(e)R^(f))_(p)C(O)OR⁴³,    -   11) (CR^(e)R^(f))_(p)R⁴³,    -   12) (CR^(e)R^(f))_(p)S(O)₀₋₂R⁶⁰,    -   13) (CR^(e)R^(f))_(p)S(O)₀₋₂N(R⁴³R⁴⁴),    -   14) OS(O)₀₋₂R⁶⁰,    -   15) N(R⁴³)C(O)R⁴⁴,    -   16) N(R⁴³)S(O)₀₋₂R⁶⁰,    -   17) (CR^(e)R^(f))_(p)N(R⁴³)R⁶⁰,    -   18) (CR^(e)R^(f))_(p)N(R⁴³)R⁶⁰OR⁴⁴,    -   19) (CR^(e)R^(f))_(p)N(R⁴³) (CR^(g)R^(h))_(q)C(O)N(R⁴⁴R⁴⁵),    -   20) N(R⁴³) (CR^(e)R^(f))_(p)R⁶⁰,    -   21) N(R⁴³) (CR^(e)R^(f))_(p)N(R⁴⁴R⁴⁵), and    -   22) (CR^(e)R^(f))_(p)C(O)N(R⁴³R⁴⁴),    -   or R² and R⁸ are independently as defined above, and R⁹ and R¹⁰,        together with the atoms to which they are attached, form the        ring

-   -   where R^(m) is C₁₋₆alkyl;        R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i),        R^(j), R^(k), and R^(l) are independently selected from the        group consisting of:    -   1) hydrogen,    -   2) C₁-C₆ alkyl,    -   3) halogen,    -   4) aryl,    -   5) R⁸⁰,    -   6) C₃-C₁₀ cycloalkyl, and    -   7) OR⁴,    -   said alkyl, aryl, and cycloalkyl being unsubstituted,        monosubstituted with R⁷, disubstituted with R⁷ and R¹⁵,        trisubstituted with R⁷, R¹⁵ and R¹⁶, or tetrasubstituted with        R⁷, R¹⁵, R¹⁶ and R¹⁷;        R⁴, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹,        R⁵², and R⁵³ and are independently selected from the group        consisting of    -   1) hydrogen,    -   2) C₁-C₆ alkyl,    -   3) C₃-C₁₀ cycloalkyl,    -   4) aryl,    -   5) R⁸¹,    -   6) CF₃,    -   7) C₂-C₆ alkenyl, and    -   8) C₂-C₆ alkynyl,    -   said alkyl, aryl, and cycloalkyl is unsubstituted,        mono-substituted with R¹⁸, di-substituted with R¹⁸ and R¹⁹,        tri-substituted with R¹⁸, R¹⁹ and R²⁰, or tetra-substituted with        R¹⁸, R¹⁹, R²⁰ and R²¹;        R⁶, R⁶⁰, R⁶¹, R⁶² and R⁶³ are independently selected from the        group consisting of    -   1) C₁-C₆ alkyl,    -   2) aryl,    -   3) R⁸³, and    -   4) C₃-C₁₀ cycloalkyl;    -   said alkyl, aryl, and cycloalkyl is unsubstituted,        mono-substituted with R²⁶, di-substituted with R²⁶ and R²⁷,        tri-substituted with R²⁶, R²⁷ and R²⁸, or tetra-substituted with        R²⁶, R²⁷, R²⁸ and R²⁹;        R⁷, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶,        R²⁷, R²⁸, and R²⁹ are independently selected from the group        consisting of    -   1) C₁-C₆ alkyl,    -   2) halogen,    -   3) OR⁵¹,    -   4) CF₃,    -   5) aryl,    -   6) C₃-C₁₀ cycloalkyl,    -   7) R⁸⁴,    -   8) S(O)₀₋₂N(R⁵¹R⁵²),    -   9) C(O)OR⁵¹,    -   10) C(O)R⁵¹,    -   11) CN,    -   12) C(O)N(R⁵¹R⁵²),    -   13) N(R⁵¹)C(O)R⁵²,    -   14) S(O)₀₋₂R⁶³,    -   15) NO₂, and    -   16) N(R⁵¹R⁵²);        R⁸⁰, R⁸¹, R⁸², R⁸³ and R⁸⁴ are independently selected from a        group of unsubstituted or substituted heterocyclic rings        consisting of a 4-6 membered unsaturated or saturated monocyclic        ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the        group consisting N, O and S, and a 9- or 10-membered unsaturated        or saturated bicyclic ring with 1, 2, 3 or 4 heteroatom ring        atoms selected from the group consisting or N, O or S; and        n, p, q, r, and s are independently 0, 1, 2, 3, 4, 5 or 6;        provided that    -   when R⁹ is OCH₃, R¹ is CH₃ and R⁵ is C(CH₃)₃, then A is        substituted,    -   when R⁹ is hydrogen, R¹ is CH₃, and R⁵ is hydrogen, then A is        substituted,    -   when R⁹ is hydrogen, R¹ is CH₃, and R⁵ is C(CH₃)₃, then A is        substituted, provided the substituent is not CH₃, and    -   when R⁹ is OCH₃, R¹ is CH₃, R⁵ is CH₃, then A is substituted.

In a class of compounds of the invention, or pharmaceutically acceptablesalts thereof, A is an aryl ring selected from phenyl, unsubstituted orsubstituted as defined above, or a heteroaryl ring, unsubstituted orsubstituted as defined above, selected from the group consisting ofpyridine, pyrimidine, pyrazine, pyridazine, indole, pyrrolopyridine,benzimidazole, benzoxazole, benzothiazole, and benzoxadiazole;

R², R⁸, R⁹ and R¹⁰ are independently selected from the group consistingof:

-   -   1) hydrogen,    -   2) halogen,    -   3) OR⁴³,    -   4) (CR^(e)R^(f))_(p)R⁴³,    -   5) CN, and    -   6) (CR^(e)R^(f))_(p)C(O)N(R⁴³R⁴⁴),    -   or R² and R⁸ are independently as defined above, and R⁹ and R¹⁰,        together with the atoms to which they are attached, form the        ring

-   -   where R^(m) is C₁₋₆alkyl;        R¹ is selected from the group consisting of    -   1) hydrogen,    -   2) (CR^(a)R^(b))₁₋₂R⁴⁰    -   3) (CR^(a)R^(b))₁₋₂OR⁴⁰,    -   4) (CR^(a)R^(b))₁₋₂N(R⁴⁰R⁴¹),    -   5) (CR^(a)R^(b))₁₋₂N(R⁴⁰)C(O)OR⁴¹,    -   6) (CR^(a)R^(b))₁₋₂N(R⁴⁰) (CR^(c)R^(d))₂N(R⁴¹)C(O)R⁴⁹,    -   7) (CR^(a)R^(b))₁₋₂C(O)OR⁴⁰,    -   8) (CR^(a)R^(b))₁₋₂N(R⁴⁰) (CR^(c)R^(d))₁₋₃R⁴¹, and    -   9) cyclopropyl; and        R⁵ is selected from the group consisting of    -   1) hydrogen,    -   2) halogen,    -   3) S(O)₀₋₂N(R⁵³R⁵⁰),    -   4) S(O)₀₋₂R⁶²,    -   5) CH₃,    -   6) C₃-C₆ alkyl,    -   7) C₃-C₁₀ cycloalkyl,    -   8) R⁸²,    -   said alkyl, aryl, and cycloalkyl is unsubstituted,        mono-substituted with R²², di-substituted with R²² and R²³,        tri-substituted with R²², R²³ and R²⁴, or tetra-substituted with        R²², R²³, R²⁴ and R²⁵,        or R¹ and R⁵ together with the atoms to which they are attached,        form a ring selected from the group of structures consisting of

-   -   where u is 0 or 1, R⁹⁹ is hydrogen or —OH, and X is O or        =NOH;

In a subclass of this class of compounds of the invention, orpharmaceutically acceptable salts thereof,

R², R⁸, R⁹ and R¹⁰ are independently selected from the group consistingof:

-   -   1) hydrogen,    -   2) halogen,    -   3) OR⁴³, and    -   4) (CR^(e)R^(f))_(p)C(O)N(R⁴³R⁴⁴).

In a group of the subclass of compounds, or pharmaceutically acceptablesalts thereof,

R¹ is selected from the group consisting of

-   -   1) hydrogen,    -   2) (CR^(a)R^(b))₁₋₂R⁴⁰    -   3) (CR^(a)R^(b))₁₋₂OR⁴⁰, or    -   4) (CR^(a)R^(b))₁₋₂N(R⁴⁰R⁴¹);        R⁵ is selected from the group consisting of    -   1) hydrogen,    -   2) C₃-C₆ alkyl, and    -   3) CH₃,    -   said alkyl is unsubstituted, mono-substituted with R²²,        di-substituted with R²² and R²³, tri-substituted with R²², R²³        and R²⁴, or tetra-substituted with R²², R²³, R²⁴ and R²⁵;        or R¹ and R⁵ together with the atoms to which they are attached,        form a ring selected from the group of structures consisting of

-   -   where u is 1, and R⁹⁹ is hydrogen or —OH.

In a subgroup of the group of compounds, or pharmaceutically acceptablesalts thereof, A is unsubstituted phenyl, or phenyl substituted withhalogen.

In a family of the subgroup of compounds, or pharmaceutically acceptablesalts thereof,

R¹ is selected from the group consisting of —CH₃, —CH₂CH₃, —(CH₂)₂OCH₃,

—(CH₂)₂NH₂, and —(CH₂)₃NH₂, —CH₂C(O)OC(CH₃)₃; and

R⁵ is selected from the group consisting of hydrogen, —C(CH₃)₃, —CH₃,

or R¹ and R⁵ together with the atoms to which they are attached, form aring selected from the group of structures consisting of

-   -   where u is 1, and R⁹⁹ is hydrogen or —OH.

A preferred embodiment is a compound selected from the group consistingof

-   3-tert-butyl-4-(3-fluorophenyl)-6-methoxy-2-methylisoquinolin-1(2H)-one,-   3-tert-butyl-4-(4-fluorophenyl)-6-methoxy-2-methylisoquinolin-1(2H)-one,-   6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,-   4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one,-   4-(4-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one,-   (1E)-11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione    1-oxime,-   3-tert-butyl-6-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one,-   2,3-dimethyl-4-phenylisoquinolin-1(2H)-one,-   3-tert-butyl-2-ethyl-6-methoxy-4-phenylisoquinolin-1(2H)-one,-   3-tert-butyl-6-methoxy-4-phenylisoquinolin-1(2H)-one,-   2-ethyl-6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one,-   6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one,-   6-methoxy-2-(2-methoxyethyl)-3-methyl-4-phenylisoquinolin-1    (2H)-one,-   2-(2-aminoethyl)-6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one,-   2-(3-aminopropyl)-6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one,-   3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile,-   3-tert-butyl-8-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one,-   3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carboxamide,-   3-tert-butyl-2-methyl-4-phenyl-6-(4-phenylbutoxy)isoquinolin-1(2H)-one,-   3-tert-butyl-2-methyl-4-phenyl-6-[(5-phenylpentyl)oxy]isoquinolin-1(2H)-one,-   11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione,-   (+/−)-11-(3-fluorophenyl)-1-hydroxy-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one,-   (1S)-11-(3-fluorophenyl)-1-hydroxy-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one,-   (1R)-11-(3-fluorophenyl)-1-hydroxy-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one,    and-   11-(3-fluorophenyl)-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one,    or a pharmaceutically acceptable salt thereof.

The above-listed compounds are active in one or more of the assays forKv1.5 described below.

Another embodiment of the invention is a method of treating orpreventing a condition in a mammal, the treatment or prevention of whichis effected or facilitated by K_(v)1.5 inhibition, which comprisesadministering an amount of a compound of Formula I that is effective atinhibiting K_(v)1.5.

A preferred embodiment is a method of treating or preventing cardiacarrhythmias, e.g. atrial fibrillation, atrial flutter, atrialarrhythmia, and supraventricular tachycardia, in a mammal, whichcomprises administering a therapeutically effective amount of a compoundof Formula I.

Another preferred embodiment is a method of preventing thromboembolicevents, such as stroke.

Another preferred embodiment is a method of preventing congestive heartfailure.

Another preferred embodiment is a method of treating or preventingimmunodepression or a disorder involving immunodepression, such as AIDS,cancer, senile dementia, trauma (including wound healing, surgery andshock) chronic bacterial infection, certain central nervous systemdisorders, and conditions including resistance by transplantation oforgans or tissue, graft-versus-host diseases brought about by medullaossium transplantation. Within this embodiment is a method for treatingor preventing immunodepression by administering a compound of theinvention with an immunosuppresant compound.

Another preferred embodiment is a method of treating or preventinggliomas including those of lower and higher malignancy, preferably thoseof higher malignancy.

Another preferred embodiment is a method for inducing in a patienthaving atrial fibrillation, a condition of normal sinus rhythm, in whichthe induced rhythm corresponds to the rhythm that would be considerednormal for an individual sharing with the patient similar size and agecharacteristics, which comprises treating the patient with a compound ofthe invention.

Another preferred embodiment is a method for treating tachycardia,(i.e., rapid heart rate e.g. 100 beats per minute) in a patient whichcomprises treating the patient with an antitachycardia device (e.g. adefibrillator or a pacemaker) in combination with a compound of Claim 1.

The present invention also encompasses a pharmaceutical formulationcomprising a pharmaceutically acceptable carrier and the compound ofFormula I or a pharmaceutically acceptable crystal form or hydratethereof. A preferred embodiment is a pharmaceutical composition of thecompound of Formula I, comprising, in addition, a second agent.

The compounds of the present invention may have asymmetric centers orasymmetric axes, and this invention includes all of the optical isomersand mixtures thereof. Unless specifically mentioned otherwise, referenceto one isomer applies to both isomers.

In addition compounds with carbon-carbon double bonds may occur in Z-and E-forms with all isomeric forms of the compounds being included inthe present invention.

As used herein except where noted, “alkyl” is intended to include bothbranched- and straight-chain saturated aliphatic hydrocarbon groups,including all isomers, having the specified number of carbon atoms.Commonly used abbreviations for alkyl groups are used throughout thespecification, e.g. methyl may be represented by “Me” or CH₃, ethyl maybe represented by “Et” or CH₂CH₃, propyl may be represented by “Pr” orCH₂CH₂CH₃, butyl may be represented by “Bu” or CH₂CH₂CH₂CH₃, etc. “C₁₋₆alkyl” (or “C₁-C₆ alkyl”) for example, means linear or branched chainalkyl groups, including all isomers, having the specified number ofcarbon atoms. C₁₋₆ alkyl includes all of the hexyl alkyl and pentylalkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl,ethyl and methyl. “C₁₋₄ alkyl” means n-, iso-, sec- and t-butyl, n- andisopropyl, ethyl and methyl. The term “alkoxy” represents a linear orbranched alkyl group of indicated number of carbon atoms attachedthrough an oxygen bridge.

The term “alkenyl” includes both branched and straight chain unsaturatedhydrocarbon groups containing at least two carbon atoms joined by adouble bond. The alkene ethylene is represented, for example, by“CH₂CH₂” or alternatively, by “H₂C═CH₂”. “C₂₋₅ alkenyl” (or “C₂-C₅alkenyl”) for example, means linear or branched chain alkenyl groupshaving from 2 to 5 carbon atoms and includes all of the pentenyl isomersas well as 1-butenyl, 2-butenyl, 3-butenyl, 1-propenyl, 2-propenyl, andethenyl (or ethylenyl). Similar terms such as “C₂₋₃ alkenyl” have ananalogous meaning.

The term “alkynyl” includes both branched and straight chain unsaturatedhydrocarbon groups containing at least two carbon atoms joined by atriple bond. The alkyne acetylene is represented, for example, by “CHCH”or alternatively, by “HC≡CH”. “C₂₋₅ alkynyl” (or “C₂-C₅ alkynyl”) forexample, means linear or branched chain alkynyl groups having from 2 to5 carbon atoms and includes all of the pentynyl isomers as well as1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, 2-propynyl, and ethynyl (oracetylenyl). Similar terms such as “C₂₋₃ alkynyl” have an analogousmeaning.

Unless otherwise noted, alkyl, alkenyl and alkynyl groups areunsubstituted or substituted with 1 to 3 substituents on each carbonatom, with halo, C₁-C₂₀ alkyl, CF₃, NH₂, N(C₁-C₆ alkyl)₂, NO₂, oxo, CN,N₃, —OH, —O(C₁-C₆ alkyl), C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, (C₀-C₆ alkyl) S(O)₀₋₂—, (C₀-C₆ alkyl)S(O)₀₋₂(C₀-C₆ alkyl)-,(C₀-C₆ alkyl)C(O)NH—, H₂N—C(NH)—, —O(C₁-C₆ alkyl)CF₃, (C₀-C₆alkyl)C(O)—, (C₀-C₆ alkyl)OC(O)—, (C₀-C₆ alkyl)O(C₁-C₆ alkyl)-, (C₀-C₆alkyl)C(O)₁₋₂(C₀-C₆ alkyl)-, (C₀-C₆ alkyl)OC(O)NH—, aryl, aralkyl,heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl,halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl,cyano-heterocycle and cyano-heterocyclylalkyl.

The term “C₀” as employed in expressions such as “C₀₋₆ alkyl” means adirect covalent bond. Similarly, when an integer defining the presenceof a certain number of atoms in a group is equal to zero, it means thatthe atoms adjacent thereto are connected directly by a bond. Forexample, in the structure

wherein w is an integer equal to zero, 1 or 2, the structure is

when w is zero.

The term “C₃₋₈ cycloalkyl” (or “C₃-C₈ cycloalkyl”) means a cyclic ringof an alkane having three to eight total carbon atoms (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl). The terms “C₃₋₇ cycloalkyl”, “C₃₋₆ cycloalkyl”, “C₅₋₇cycloalkyl” and the like have analogous meanings.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively referred to as fluoro (F), chloro (Cl), bromo(Br), and iodo (I)).

The term “C₁₋₆ haloalkyl” (which may alternatively be referred to as“C₁-C₆ haloalkyl” or “halogenated C₁-C₆ alkyl”) means a C₁ to C₆ linearor branched alkyl group as defined above with one or more halogensubstituents. The term “C₁₋₄ haloalkyl” has an analogous meaning. Theterm “C₁₋₆ fluoroalkyl” has an analogous meaning except that the halogensubstituents are restricted to fluoro. Suitable fluoroalkyls include theseries (CH₂)₀₋₄CF₃ (i.e., trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoro-n-propyl, etc.).

The term “carbocycle” (and variations thereof such as “carbocyclic” or“carbocyclyl”) as used herein, unless otherwise indicated, refers to (i)a C₃ to C₈ monocyclic, saturated or unsaturated ring or (ii) a C₇ to C₁₂bicyclic saturated or unsaturated ring system. Each ring in (ii) iseither independent of, or fused to, the other ring, and each ring issaturated or unsaturated. The carbocycle may be attached to the rest ofthe molecule at any carbon atom which results in a stable compound. Thefused bicyclic carbocycles are a subset of the carbocycles; i.e., theterm “fused bicyclic carbocycle” generally refers to a C₇ to C₁₀bicyclic ring system in which each ring is saturated or unsaturated andtwo adjacent carbon atoms are shared by each of the rings in the ringsystem. A fused bicyclic carbocycle in which one ring is saturated andthe other is saturated is a saturated bicyclic ring system. A fusedbicyclic carbocycle in which one ring is benzene and the other issaturated is an unsaturated bicyclic ring system. A fused bicycliccarbocycle in which one ring is benzene and the other is unsaturated isan unsaturated ring system. Saturated carbocyclic rings are alsoreferred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.Unless otherwise noted, carbocycle is unsubstituted or substituted withC₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, aryl, halogen, NH₂ or OH. Asubset of the fused bicyclic unsaturated carbocycles are those bicycliccarbocycles in which one ring is a benzene ring and the other ring issaturated or unsaturated, with attachment via any carbon atom thatresults in a stable compound. Representative examples of this subsetinclude the following:

The term “aryl” refers to aromatic mono- and poly-carbocyclic ringsystems, wherein the individual carbocyclic rings in the poly ringsystems are fused or attached to each other via a single bond. Suitablearyl groups include phenyl, naphthyl, and biphenylenyl.

The term “heterocycle” (and variations thereof such as “heterocyclic” or“heterocyclyl”) broadly refers to (i) a stable 4- to 8-membered,saturated or unsaturated monocyclic ring, or (ii) a stable 7- to12-membered bicyclic ring system, wherein each ring in (ii) isindependent of, or fused to, the other ring or rings and each ring issaturated or unsaturated, and the monocyclic ring or bicyclic ringsystem contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms,or from 1 to 4 heteroatoms) selected from N, O and S and a balance ofcarbon atoms (the monocyclic ring typically contains at least one carbonatom and the ring systems typically contain at least two carbon atoms);and wherein any one or more of the nitrogen and sulfur heteroatoms isoptionally oxidized, and any one or more of the nitrogen heteroatoms isoptionally quaternized. The heterocyclic ring may be attached at anyheteroatom or carbon atom, provided that attachment results in thecreation of a stable structure. When the heterocyclic ring hassubstituents, it is understood that the substituents may be attached toany atom in the ring, whether a heteroatom or a carbon atom, providedthat a stable chemical structure results.

As used herein, the terms “substituted C₃-C₁₀ cycloalkyl”, “substitutedaryl” and “substituted heterocycle” are intended to include the cyclicgroup containing from 1 to 3 substituents in addition to the point ofattachment to the rest of the compound. Preferably, the substituents areselected from the group which includes, but is not limited to, halo,C₁-C₂₀ alkyl, CF₃, NH₂, N(C₁-C₆ alkyl)₂, NO₂, oxo, CN, N₃, —OH, —O(C₁-C₆alkyl), C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆ alkyl)S(O)₀₋₂—, (C₀-C₆ alkyl)S(O)₀₋₂(C₀-C₆ alkyl)-, (C₀-C₆ alkyl)C(O)NH—,H₂N—C(NH)—, —O(C₁-C₆ alkyl)CF₃, (C₀-C₆ alkyl)C(O)—, (C₀-C₆ alkyl)OC(O)—,(C₀-C₆alkyl)O(C₁-C₆ alkyl)-, (C₀-C₆ alkyl)C(O)₁₋₂(C₀-C₆ alkyl)-, (C₀-C₆alkyl)OC(O)NH—, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halo-aryl,halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl,cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl.

Saturated heterocyclics form a subset of the heterocycles; i.e., theterm “saturated heterocyclic” generally refers to a heterocycle asdefined above in which the entire ring system (whether mono- orpoly-cyclic) is saturated. The term “saturated heterocyclic ring” refersto a 4- to 8-membered saturated monocyclic ring or a stable 7- to12-membered bicyclic ring system which consists of carbon atoms and oneor more heteroatoms selected from N, O and S. Representative examplesinclude piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl(or tetrahydrofuranyl).

Heteroaromatics form another subset of the heterocycles; i.e., the term“heteroaromatic” (alternatively “heteroaryl”) generally refers to aheterocycle as defined above in which the entire ring system (whethermono- or poly-cyclic) is an aromatic ring system. The term“heteroaromatic ring” refers a 5- or 6-membered monocyclic aromatic ringor a 7- to 12-membered bicyclic which consists of carbon atoms and oneor more heteroatoms selected from N, O and S. Representative examples ofheteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, and thiadiazolyl.

Representative examples of bicyclic heterocycles include benzotriazolyl,indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl,quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl,quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl (i.e.,

imidazo(2,1-b)(1,3)thiazole, (i.e.,

and benzo-1,3-dioxolyl (i.e.,

In certain contexts herein,

is alternatively referred to as phenyl having as a substituentmethylenedioxy attached to two adjacent carbon atoms.

Unless expressly stated to the contrary, an “unsaturated” ring is apartially or fully unsaturated ring. For example, an “unsaturatedmonocyclic C₆ carbocycle” refers to cyclohexene, cyclohexadiene, andbenzene.

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heterocycle described as containing from “1 to4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4heteroatoms.

When any variable occurs more than one time in any constituent or in anyformula depicting and describing compounds of the invention, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

The term “substituted” (e.g., as in “aryl which is optionallysubstituted with one or more substituents . . . ”) includes mono- andpoly-substitution by a named substituent to the extent such single andmultiple substitution (including multiple substitution at the same site)is chemically allowed.

In compounds of the invention having pyridyl N-oxide moieties, thepyridyl-N-oxide portion is structurally depicted using conventionalrepresentations such as

which have equivalent meanings.

For variable definitions containing terms having repeated terms, e.g.,(CR^(i)R^(j))_(r), where r is the integer 2, R^(i) is a definedvariable, and R^(j) is a defined variable, the value of R^(i) may differin each instance in which it occurs, and the value of R^(j) may differin each instance in which it occurs. For example, if R^(i) and R^(j) areindependently selected from the group consisting of methyl, ethyl,propyl and butyl, then (CR^(i)R^(j))₂ can be

Pharmaceutically acceptable salts include both the metallic (inorganic)salts and organic salts; a list of which is given in Remington'sPharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well knownto one skilled in the art that an appropriate salt form is chosen basedon physical and chemical stability, flowability, hydro-scopicity andsolubility. As will be understood by those skilled in the art,pharmaceutically acceptable salts include, but are not limited to saltsof inorganic acids such as hydrochloride, sulfate, phosphate,diphosphate, hydrobromide, and nitrate or salts of an organic acid suchas malate, maleate, fumarate, tartrate, succinate, citrate, acetate,lactate, methanesulfonate, p-toluenesulfonate or palmoate, salicylateand stearate. Similarly pharmaceutically acceptable cations include, butare not limited to sodium, potassium, calcium, aluminum, lithium andammonium (especially ammonium salts with secondary amines). Preferredsalts of this invention for the reasons cited above include potassium,sodium, calcium and ammonium salts. Also included within the scope ofthis invention are crystal forms, hydrates and solvates of the compoundsof Formula I.

Methods for preparing the compounds of this invention are illustrated inthe following schemes, in which variables R¹, R⁵ and R⁹ are as definedabove, and variable R³ is a substituent selected from the group ofsubstituents listed above as possible substituents when A is asubstituted aryl ring. Other synthetic protocols will be readilyapparent to those skilled in the art.

The following examples illustrate the preparation of the compounds ofFormula I and as such are not to be considered as limiting the inventionset forth in the claims appended hereto.

Example 1

11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione

To a mixture of 2-(3-fluorobenzoyl)-4-methoxybenzoyl chloride (3.36 g)and piperidin-3-one hydrochloride (1.88 g) in 54 ml of toluene was added2,6-lutidine (4.01 ml). The reaction was heated at reflux (3:10 pm) for24 h, then partitioned between EtOAc and 400 mL of 1 N HCl. The aqueoussolution was extracted twice more with EtOAc. The combined organicsolutions were dried (MgSO₄) and concentrated. Flash chromatography(40-100% EtOAc/hexanes) to gave the titled compound.

HRMS (ES): calcd: 338.1187. found: 338.1188.

Example 2

11-(3-fluorophenyl)-1-hydroxy-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one

To a solution of11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dionein 5 mL 1:1 MeOH:CH₂Cl₂ was added NaBH₄ (17 mg). The reaction wasstirred at room temp for 1 h, then diluted with bicarb and EtOAc andstirred for 30 min. The mixture was extracted once with EtOAc, and theorganic solution was washed once with brine, dried (Na₂SO₄) andconcentrated. Flash chromatography (40 g silica, 50-100% EtOAc/hexanes)gave the titled compound.

HRMS (ES): calcd: 340.1343. found: 340.1353.

11-(3-fluorophenyl)-1-hydroxy-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-onewas resolved into its constituent enantiomers by chiral HPLC. The twopure enantiomers were identical to the racemic compound by HRMS and NMR.

Example 3

11-(3-fluorophenyl)-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one

Step A

A suspension of11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dionein 2 ml of THF and 2 mL of TMEDA was cooled to 0 C and treated lithiumdiisopropylamide solution (Aldrich, 2 M, 0.445 mL). After stirring for 1h, a solution of Tf₂NPh in 2 ml THF/2 ml TMEDA was added via cannula.The reaction was warmed to room temp and stirred for 2 h, thenpartitioned between CH₂Cl₂ and pH 7 buffer. The aqueous solution wasextracted once more with CH₂Cl₂. The combined organic solutions weredried (Na₂SO₄) and concentrated, then purified by flash chromatography(40 g silica, 30-90% EtOAc/hexanes) to give 57 mg of11-(3-fluorophenyl)-9-methoxy-6-oxo-3,6-dihydro-4H-pyrido[1,2-b]isoquinolin-1-yltrifluoromethanesulfonate.

Step B

To a suspension of11-(3-fluorophenyl)-9-methoxy-6-oxo-3,6-dihydro-4H-pyrido[1,2-b]isoquinolin-1-yltrifluoromethanesulfonate in EtOH (4 ml) and EtOAc (2 mL) was added PtO₂as a slurry in EtOH. The reaction was stirred at room temp under an H₂balloon for 16 h. The mixture was filtered through celite andconcentrated. Flash chromatography (40 g silica, 30-80% EtOAc/hexanes)gave the titled compound.

HRMS (ES): calcd: 324.1395. found: 324.1394.

Example 4

(1E)-11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione1-oxime

To a solution of11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione(125 mg) in 4 mL pyridine was added hydroxylamine hydrochloride (51 mg).The reaction was heated to reflux for 5 h, then cooled to room temp andpartitioned between ether and water. The aqueous solution was extractedwith ether (2×). The combined organic solutions were washed with 1 N HCl(1×), and 10% bicarb (1×), then dried (MgSO₄) and concentrated. Flashchromatography (10-70% EtOAc/hexanes) gave the titled compound.

HRMS (ES): calcd: 353.1296. found: 353.1305.

Example 5

2,3-Dimethyl-4-phenyl-2H-isoquinolin-1-one

Step A

To a stirred solution of α-phenyl-o-toluic acid (2.0 g, 9.43 mmol) inmethylene chloride (500 mL) at room temperature under argon was added bydropwise addition a solution of oxalyl chloride (0.988 mL, 11.3 mmol) inmethylene chloride (50 mL). N,N-Dimethylformamide (10 drops) were addedand the contents of the reaction flask were stirred 1.5 h. Solvent wasremoved in vacuo and methylene chloride (100 mL) and methylaminehydrochloride (950 mg, 14.1 mmol) was added. With ice-bath cooling asolution of N,N-diisopropylethylamine (4.10 mL, 23.6 mmol) in methylenechloride (10 mL) was added dropwise. Saturated sodium bicarbonate wasadded and the resulting mixture extracted with methylene chloride (3×).The combined organic extracts were dried with sodium sulfate (anh.).Filtration followed by removal of the solvent in vacuo gave a solidwhich after trituration with ether afforded N-Methyl-2-(phenylmethyl)benzamide (974 mg, 4.23 mol, 46%). MS [M+H]⁺226

Step B

To an isopropanol/dry ice cooled solution of N-Methyl-2-(phenylmethyl)benzamide (1.00 g, 4.44 mmol) in THF (20 mL) under argon was addedn-butyllithium solution (2.5M, 4.44 mL, 11.1 mmol) dropwise. After 10min. neat acetyl chloride (0.447 mL, 6.66 mmol) was slowly added to thereaction solution. The contents of the reaction flask were allowed towarm to room temperature and after 2 h the reaction was quenched withsaturated ammonium chloride. The mixture was extracted with ether (3×)and then the combined organic portions were washed with brine and driedwith anhydrous sodium sulfate. Filtration followed by evaporation ofsolvent in vacuo gave the crude product which was subjected to flashcolumn chromatography (hexane:ethyl acetate 70:30 then 50:50) to affordthe title compound as a white solid.

MS [M+H]⁺250

¹HNMR (CHCl₃, 300 MHz) δ 8.48 (m, 1H); 7.54-7.38 (m, 5H); 7.28-7.20 (m,2H); 6.98 (m, 1H), 3.70 (s, 3H); 2.21 (s, 3H).

Example 6

3-tert-Butyl-6-hydroxy-2-methyl-4-phenyl-2H-isoquinolin-1-one

To a methylene chloride (5 mL) solution of3-tert-butyl-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (100 mg,0.311 mmol) under argon at −70° C. was added boron tribromide (1.0M,0.934 mL, 0.934 mmol). The contents of the reaction flask were warmed toroom temperature and stirred 24 h. Extracted with methylene chloride(3×), then the combined organic extracts were washed with brine anddried with anhydrous sodium sulfate. Filtration followed by evaporationof solvent in vacuo gave a solid which was triturated with ethanol.Recrystallization from ethyl acetate/ethanol afforded the titlecompound.

MS [M+H]⁺308

¹HN MR (CDCl₃, 300 MHz) δ 9.21 (s, 1H); 8.27 (d, 1H); 7.45-7.25 (m, 3H);7.28-7.22 (m, 2H), 6.95 (dd, 1H); 6.23 (m, 1H); 3.74 (s, 3H); 1.35 (s,9H).

Example 7

6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one

Step A

A solution of 2-benzyl-4-methoxy-N-methylbenzamide (125 mg) in 5 mL THFwas cooled to −78 C. n-BuLi (0.400 mL, 2.5 M in hexanes) was added, andthe reaction was stirred at −78 C for 20 min. A solution of ethylformate (0.160 mL) in 1 mL THF was added via cannula. The reaction wasquenched at −78 C by addition of saturated aqueous ammonium acetate. Themixture was extracted with EtOAc and concentrated to give4-methoxy-N-methyl-2-(2-oxo-1-phenylethyl)benzamide, which was usedwithout further purification.

Step B

4-methoxy-N-methyl-2-(2-oxo-1-phenylethyl)benzamide (100 mg) wasdissolved in 2 mL of phosphoric acid with gentle heating. After asolution was obtained, the reaction was partitioned between water andEtOAc. The organic solution was dried (Na₂SO₄) and concentrated. Flashchromatography (25% EtOAc in CH₂Cl₂) provided the titled compound as awhite solid.

[M+H]⁺ calcd: 266. found: 266 (FAB).

Example 8

4(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one

Step A

To a −78 C solution of 4-methoxy-N-methylbenzamide (2.0 g) in THF wasadded n-BuLi (10 mL, 2.5 M in hexanes). The reaction was stirred for 10min at −78° C., warmed to 0 C, then cooled back to −78 C.3-fluorobenzaldehyde (1.90 mL) was added as a solution in THF viacannula. The reaction was warmed to room temp, then quenched withsaturated aqueous NH₄Cl. The mixture was extracted with EtOAc,concentrated, and purified by flash chromatography (5% MeOH in CH₂Cl₂)to give 2-[(3-fluorophenyl)(hydroxy)methyl]-4-methoxy-N-methylbenzamide.

Step B

To a solution of2-[(3-fluorophenyl)(hydroxy)methyl]-4-methoxy-N-methylbenzamide (500 mg)in methanol was added 500 mg of Pd/C (10%). The reaction was stirredovernight under H₂ (1 atm), then filtered through celite andconcentrated to give 2-(3-fluorobenzyl)-4-methoxy-N-methylbenzamide,which was used without further purification.

Step C

To a −78 C solution of 2-(3-fluorobenzyl)-4-methoxy-N-methylbenzamide(500 mg) in 15 mL THF was added n-BuLi (1.64 mL, 2.5 M in hexanes)dropwise. After 10 min, acetyl chloride (170 mg) was added as a solutionin 2 mL THF. The cooling bath was removed, and the reaction was stirredfor 2 h. The reaction was quenched with saturated aqueous NH₄Cl andextracted with EtOAc. The organic solution was concentrated and treatedwith phosphoric acid and minimal CH₂Cl₂ until a solution was obtained.Removal of CH₂Cl₂ was followed by addition of bicarb/EtOAc to neutralizethe reaction. The mixture was extracted with EtOAc, concentrated, andpurified by flash chromatography (20% EtOAc in CH₂Cl₂) to give a solid,which was triturated with EtOAc to give the titled compound.

[M]⁺ calcd: 297. found: 297 (EI).

Example 9

4-(4-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one

Following the procedure for4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one, using(in Step A) 4-fluorobenzaldehyde in place of 3-fluorobenzaldehyde, thetitle compound was synthesized.

[M]⁺ calcd: 297. found: 297 (EI).

Example 10

3-tert-butyl-4-(3-fluorophenyl)-6-methoxy-2-methylisoquinolin-1(2H)-one

Following the procedure for4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one, using(in Step C) pivaloyl chloride in place of acetyl chloride, and heating(in Step C) the final phosphoric acid solution to 100 C, the titlecompound was synthesized.

[M]⁺ calcd: 339. found: 339 (EI).

Example 11

3-tert-butyl-4-(4-fluorophenyl)-6-methoxy-2-methylisoquinolin-1(2H)-one

Following the procedure for4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one, using(in Step A) 4-fluorobenzaldehyde in place of 3-fluorobenzaldehyde, using(in Step C) pivaloyl chloride in place of acetyl chloride, and heating(in Step C) the final phosphoric acid solution to 100 C, the titlecompound was synthesized.

[M]⁺ calcd: 339. found: 339 (EI).

Example 12

3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile

Step A

A mixture of3-tert-butyl-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (0.333 g)and 48% HBr (30 mL) was heated at reflux for 8 h. The reaction wasconcentrated to give3-tert-butyl-6-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one as a brownsolid, which was used without further purification.

Step B

To a solution of3-tert-butyl-6-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one (210 mg)in 7 mL DMP were added potassium carbonate (281 mg) and N-phenyltriflimide (731 mg). The reaction was stirred at room temp for 90 min,then partitioned between water and EtOAc. The organic solution was dried(Na₂SO₄) and concentrated, then purified by flash chromatography (20%EtOAc in hexanes) to give 175 mg of3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yltrifluoromethanesulfonate.

Step C

A solution of3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yltrifluoromethanesulfonate (225 mg) in 3 mL DMF was sparged with Argonfor 10 min. Zn(CN)₂ (250 mg) and Pd(PPh₃)₄ (100 mg) were added, and thereaction was heated at 80 C for 5 h, then partitioned between tolueneand 2 N NaOH. The organic solution was washed with 2 N NaOH (2×), thendried (Na₂SO₄) and concentrated. Flash chromatography (20% EtOAc inhexanes) gave the titled compound.

Elemental analysis calcd for C₂₁H₂₀N₂O-0.45H₂O-0.05 EtOAc: C, 77.41; H,6.53; N, 8.52. found: C, 77.36; H, 6.45; N, 8.53.

Example 13

3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carboxamide

3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile(300 mg), 10 N NaOH (6 mL), and methanol (1 mL) were combined at heatedat 110 C overnight. The reaction was acidified with 6 N HCl to give aprecipitate, which was isolated by filtration. This material waspartitioned between EtOAc and 1 N NaOH by stirring vigorously overnight.The organic solution was discarded, and the aqueous solution was allowedto stand overnight, during which time a precipitate formed. Filtrationprovided the titled compound.

[M+H]⁺ calcd: 335. found: 335 NAB).

Example 14

3-tert-butyl-2-methyl-4-phenyl-6-(4-phenylbutoxy)isoquinolin-1(2H)-one

A solution of3-tert-butyl-6-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one (50 mg),4-phenyl-1-iodobutane (100 mg) and cesium carbonate (100 mg) in DMF (2.5mL) was heated at 80 C for 6 h. The reaction was partitioned betweenwater and EtOAc. The organic solution was dried (Na₂SO₄) andconcentrated, then purified by flash chromatography (20% EtOAc inhexanes) to give the titled compound.

[M+H]⁺ calcd: 440. found: 440 (FAB).

Example 15

3-tert-butyl-2-methyl-4-phenyl-6-[(5-phenylpentyl)oxy]isoquinolin-1(2H)-one

Following the procedure for3-tert-butyl-2-methyl-4-phenyl-6-(4-phenylbutoxy)isoquinolin-1(2H)-one,using 5-phenyl-1-iodopentane in place of 4-phenyl-1-iodobutane, thetitled compound was obtained.

¹H NMR (CDCl₃, 300 MHz) δ 8.34 (d, J=9 Hz, 1H); 7.40 (m, 2H); 7.29-7.14(m, 8H); 6.95 (dd, J=9.2 Hz, 1H); 6.14 (d, J=2 Hz, 1H); 3.75 (s, 3H);3.71-3.75 (m, 2H); 2.59 (t, J=8 Hz, 2H); 1.72-1.56 (m, 4H); 1.44-1.33(m, 2H); 1.27 (s, 9H)

Example 16

3-tert-butyl-8-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one

Step A

Following the procedure for4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one, using(in Step A) 2-methoxy-N-methylbenzamide in place of4-methoxy-N-methylbenzamide, using (in Step C) pivaloyl chloride inplace of acetyl chloride, and heating (in Step C) the final phosphoricacid solution to 100 C,3-tert-butyl-8-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one wassynthesized.

Step B

A mixture of3-tert-butyl-8-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (0.500 g)and 48% HBr (15 mL) was heated at reflux overnight. The reaction wasconcentrated and purified by flash chromatography (10% EtOAc in hexanes)to give the titled compound.

Elemental analysis calcd for C₂₀H₂₁NO₂-0.10H₂O-0.10 EtOAc: C, 77.04; H,6.97; N, 4.40. found: C, 77.04; H, 6.97; N, 4.40.

Example 17

3-tert-butyl-2-ethyl-6-methoxy-4-phenylisoquinolin-1(2H)-one

Step A

To a 0 C solution of 2-benzyl-4-methoxybenzoic acid (5 g) in 250 mLCH₂Cl₂ were added a catalytic amount of DMF and a solution of oxalylchloride (2 mL) in 40 mL CH₂Cl₂. The reaction was warmed to room tempand stirred overnight, then concentrated to dryness and azeotroped fromtoluene (2×). The residue was dissolved in 50 mL THF and added dropwiseto a 0 C solution of ethylamine (10 mL, 70% aqueous solution) in 200 mLTHF. The reaction was warmed to room temp and stirred for 2 h, thenquenched with saturated aqueous KHSO₄ solution and extracted with EtOAc(2×). The organic solutions were dried (Na₂SO₄) and concentrated, thentriturated with hexanes to give 5.2 g of2-benzyl-N-ethyl-4-methoxybenzamide.

Step B

Following the procedure for4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one (Step C),using 2-benzyl-N-ethyl-4-methoxybenzamide in place of2-(3-fluorobenzyl)-4-methoxy-N-methylbenzamide, using pivaloyl chloridein place of acetyl chloride, and heating the final phosphoric acidsolution to 100 C, the titled compound was synthesized.

Elemental analysis calcd for C₂₂H₂₅NO₂-0.35H₂O: C, 77.31; H, 7.58; N,4.10. found: C, 77.32; H, 7.29; N, 3.83.

Example 18

3-tert-butyl-6-methoxy-4-phenylisoquinolin-1(2H)-one

Step A

To a solution of 2-benzyl-4-methoxybenzoic acid (14.2 g) in 600 mLCH₂Cl₂ was added a catalytic amount of DMF, followed by a solution ofoxalyl chloride (8.7 g) in 100 mL of CH₂Cl₂. The reaction was stirred atroom temp overnight, then concentrated and azeotroped with toluene (2×).The residue was dissolved in 700 mL CH₂Cl₂ and cooled to 0 C. Tert-butylamine (13.9 g) was added, and the reaction was warmed to room temp.After 1.5 h, the reaction was quenched with 5% aqueous KHSO₄. Theorganic solution was separated, washed once with saturated aqueoussodium bicarbonate, dried (Na₂SO₄) and concentrated to give 15.9 g of2-benzyl-N-tert-butyl)-4-methoxybenzamide.

Step B

A solution of 2-benzyl-N-(tert-butyl)-4-methoxybenzamide (3.1 g) in 50mL THF was sparged with Ar for 10 min. The solution was cooled to −78 C,and n-BuLi (10 mL of a 2.5 M hexanes solution) was added dropwise. Afterstirring for 1 h at −78 C, pivaloyl chloride (0.99 g) was addeddropwise. The reaction was stirred for 10 min at −78 C, then for 1 h atroom temp, then quenched with saturated aqueous NH₄Cl. The mixture wasextracted with EtOAc (3×), then the combined organic solutions werewashed with brine (1×), dried (Na₂SO₄) and concentrated. The residue wascombined with 25 mL of 80% H₃PO₄ and heated to 100 C for 3 h. Thereaction was poured into ice, then extracted with _(CH2Cl2) (3×). Theorganic solutions were washed with saturated aqueous sodium bicarbonate,dried (Na₂SO₄) and concentrated. Trituration with diethyl ether provided2.7 g of the titled compound.

Elemental analysis calcd for C₂₀H₂₁NO₂: C, 78.14; H, 6.89; N, 4.56.found: C, 77.81; H, 6.77; N, 4.65.

Example 19

2-ethyl-6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one

Following the procedure for4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one (Step C),using 2-benzyl-N-ethyl-4-methoxybenzamide in place of2-(3-fluorobenzyl)-4-methoxy-N-methylbenzamide and heating the finalphosphoric acid solution to 100 C, the titled compound was synthesized.

[M+H]⁺ calcd: 294. found: 294 (FAB)

Example 20

6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one

A solution of 2-benzyl-N-(tert-butyl)-4-methoxybenzamide (3.1 g) in 50mL THF was sparged with Ar for 10 min. The solution was cooled to −78 C,and n-BuLi (10 mL of a 2.5 M hexanes solution) was added dropwise. Afterstirring for 1 h at −78 C, acetyl chloride (0.99 g) was added dropwise.The reaction was stirred for 10 min at −78 C, then for 1 h at room temp,then quenched with saturated aqueous NH₄Cl. The mixture was extractedwith EtOAc (3×), then the combined organic solutions were washed withbrine (1×), dried (Na₂SO₄) and concentrated. The residue was combinedwith 25 mL of 80% H₃PO₄ and heated to 100 C for 3 h. The reaction waspoured into ice, then extracted with CH₂Cl₂ (3×). The organic solutionswere washed with saturated aqueous sodium bicarbonate, dried (Na₂SO₄)and concentrated. Trituration with diethyl ether provided the titledcompound.

Elemental analysis calcd for C₁₇H₁₅NO₂-1.0H₂O: C, 72.06; H, 6.05; N,4.94. found: C, 72.40; H, 5.52; N, 4.61.

Example 21

6-methoxy-2-(2-methoxyethyl)-3-methyl-4-phenylisoquinolin-1(2H)-one

A combination of 6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one (0.85g) and sodium hydride (60% dispersion in mineral oil, 240 mg) in 25 mLof DMF was heated at 60 C for 30 min, then cooled to room temp.4-bromo-1-methoxyethane (1 mL) was added via syringe, and the reactionwas stirred at room temp overnight, then quenched by addition ofsaturated aqueous NH₄Cl. The mixture was extracted with EtOAc (3×). Thecombined organic solutions were washed with water (1×) and brine (1×),then dried (Na₂SO₄) and concentrated. Flash chromatography (20%EtOAc/hexanes) gave a solid which was triturated with diethyl ether toprovide the titled compound.

Elemental analysis calcd for C₂₀H₂₁NO₃: C, 74.28; H, 6.55; N, 4.33.found: C, 74.43; H, 6.58; N, 4.18.

Example 22

3-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)propan-1-aminiumchloride

Step A

A combination of 6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one (0.85g) and sodium hydride (60% dispersion in mineral oil, 186 mg) in 25 mLof DMF was heated at 60 C for 30 min, then cooled to room temp.3-phthalimido-1-bromopropane (1 mL) was added via syringe, and thereaction was stirred at room temp overnight, then quenched by additionof saturated aqueous NH₄Cl. The mixture was extracted with EtOAc (3×).The combined organic solutions were washed with water (1×) and brine(1×), then dried (Na₂SO₄) and concentrated. Flash chromatography (20%EtOAc/hexanes) gave a solid which was triturated with diethyl ether toprovide 500 mg of2-[3-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)propyl]-1H-isoindole-1,3(2H)-dione.

Step B

2-[3-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)propyl]-1H-isoindole-1,3(2H)-dione(0.46 g) was dissolved in 20 mL methanol, and hydrazine (0.100 mL) wasadded. The reaction was stirred overnight at room temp, then dilutedwith brine and extracted with EtOAc (3×). The combined organic solutionswere dried (Na₂SO₄) and concentrated. Flash chromatography (5% MeOH inCH₂Cl₂) gave a solid, which was treated with excess HCl andrecrystallized from isopropanol/diethyl ether to give the titledcompound.

Elemental analysis calcd for C₂₀H₂₂N₂O₂—HCl: C, 66.93; H, 6.46; N, 7.81.found: C, 66.57; H, 6.41; N, 7.47.

Example 23

2-(2-aminoethyl)-6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one

Step A

Following the procedure for2-[3-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)propyl]-1H-isoindole-1,3(2H)-dione,using 2-(Boc-amino) ethyl bromide in place of3-phthalimido-1-bromopropane, tert-butyl2-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)ethylcarbamatewas obtained.

Step B

tert-butyl2-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)ethylcarbamate(800 mg) was dissolved in 200 mL EtOAc and cooled to 0 C. HCl gas wasbubbled through the solution for 5 min, and the reaction was warmed toroom temp. After stirring for 4 h, the reaction was filtered to isolatethe hydrochloride salt of the title compound as a white solid.

[M+H]⁺ calcd: 309. found: 309 (FAB).

The following additional compounds were prepared using proceduresgenerally described above, e.g. Examples 1 and 2.

Example Compound Name MS (M+1) 24

10-(3-chlorophenyl)-8- methoxy-2,3- dihydropyrrolo[1,2-b]isoquinoline-1,5-dione 340.0732 25

10-(3-chlorophenyl)-1- hydroxy-8-methoxy-2,3- dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one Enantiomer A 342.0879 26

10-(3-chlorophenyl)-1- hydroxy-8-methoxy-2,3- dihydropyrrolo[1,2-b]issoquinolin-5(1H)-one Enantiomer B 342.0879

Using the methodologies described below, representative compounds of theinvention were evaluated and found to exhibit activity in the Kv1.5assays, thereby demonstrating and confirming the utility of thecompounds of this invention as Kv1.5 inhibitors and antiarrhythmics.Compounds of this type may exhibit forward rate-dependence, blocking theoutward K⁺ currents to a greater extent or preferentially at fasterrates of depolarization or heart rates. Such a compound could beidentified in electrophysiological studies as described below. Forexample, during a train of depolarizations delivered at frequencies of 1Hz and 3 Hz, the block is “rate-dependent” if the amount of blockobserved during a 10 second train at 3 Hz is greater than that at 1 Hz.A Kv1.5 blocker may also display use-dependence, during which the blockof the outward K⁺ currents increases with use, or during repetitivedepolarization of a cardiac cell. Use dependence of block occurs to agreater extent with each successive depolarization in a train orsequence of pulses or depolarizations at a given rate or frequency. Forexample, during a train of 10 depolarizations at a frequency of 1 Hz,the block is “use-dependent” if the amount of block is greater for the10^(th) pulse than for the 1^(st) pulse of the train. A Kv1.5 blockermay exhibit both use-dependence and rate-dependence.

A Kv1.5 blocker may also be identified through electrophysiologicalstudies of native I_(Kur) using cardiac myocytes or other tissue fromvarious species including, but not limited to, human, rat, mouse, dog,monkey, ferret, rabbit, guinea pig, or goat. In native tissues Kv1.5 mayexist as a homo-oligomer, or as a hetero-oligomer with other Kv familymembers, or may exist in a complex with a β-subunit. Compounds of thisinvention may block Kv1.5 homo- or hetero-oligomers or Kv1.5 incomplexes with β-subunits.

Kv1.5 Assays

The high throughput Kv1.5 planar patch clamp assay is a systematicprimary screen. It confirms activity and provides a functional measureof the potency of agents that specifically affect Kv1.5 potassiumchannels. Kiss et al. (Assay and Drug Dev. Tech., 1(1-2): 127-135, 2003)and Schroeder et al. (J. of Biomol. Screen., 8(1);50-64, 2003) describethe use of this instrument for Kv1.5 as well as other voltage gated ionchannels.

Chinese hamster ovary cells (CHO) stably expressing the human Kv1.5potassium channel alpha subunit, cloned from human heart, are grown to90-100% confluence in Ham's F12 medium supplemented with 10% FBS, 100U/ml penicillin, 100 μg/ml streptomycin, 1000 μg/ml G-418 sulfate. Cellsare subcultured by treatment with Versene, then suspended inphosphate-buffered saline (PBS) and centrifuged The cell pellet isresuspended in PBS and the resulting suspension placed in the cellreservoir of the IonWorks™ HT instrument.

Electrophysiological recordings are performed with intracellularsolution containing (mM): K-gluconate 100, KCl 40, MgCl₂ 3.2, EGTA 3,N-2-hydroxylethylpiperazine-N¹-2-ethanesulphonic acid (HEPES) 5,adjusted to pH 7.3. Amphotericin (Sigma) is prepared as 30 mg/ml stocksolution and diluted to a final working concentration of 0.1 mg/ml ininternal buffer solution. The external solution is Dulbecco's PBS(Invitrogen) and contains (mM): CaCl₂ 0.90, KCl 2.67, KPO₄ 1.47, MgCl₂0.50, NaCl 138, NaPO₄ 8.10 and has a pH of 7.4. All compounds areprepared as 10 mM stock solutions in DMSO. Compounds are diluted intoexternal buffer, then transferred from the drug plate to the Patchplateduring the experiment (final DMSO concentration <0.66% vol.).

Kv1.5 ionic currents are recorded at room temperature. Membrane currentsare amplified (RMS ˜10 pA) and sampled at 10 kHz. Leak subtraction wasperformed in all experiments by applying a 160 ms hyperpolarizing (10mV) pre-pulses 200 ms before the test pulses to measure leakconductance. The patch clamp stimulus protocol is as follows:

-   1. Patchplate wells are loaded with 3.5 μL of external buffer.-   2. Planar micropipette hole resistances (Rp) is determined by    applying a 10 mV, 160 ms potential difference across each hole (Hole    test).-   3. Cells are pipetted into the Patchplate and form high resistance    seals with the 1-2 μm holes at the bottom of each Patchplate well. A    seal test scan is performed to determine how many of the Patchplate    wells have cells that have formed seals.-   4. In order to gain electrical access to the cells, intracellular    solution containing amphotericin is circulated for 4 minutes on the    bottom side of the Patchplate.-   5. Pre-compound addition test pulse is applied to each well on the    Patchplate. Protocol: Cells are voltage clamped at a membrane    holding potential of −80 mV for 15 seconds. This is followed by    application of a 5 Hz stimulus train (27×150 ms depolarizations to    +40 mV). The membrane potential steps to +40 mV evoke outward    (positive) ionic currents.-   6. Compound is added to each well of the Patchplate. Compounds are    allowed to incubate for 5 minutes.-   7. Post-compound addition test pulse protocol is applied. Protocol:    Cells are voltage clamped at a membrane holding potential of −80 mV    for 15 seconds. This is followed by application of a 5 Hz stimulus    train (27×150 ms depolarizations to +40 mV).

Data analysis is conducted off-line. Paired comparisons between pre-drugand post-drug additions are used to determine the inhibitory effect ofeach compound. % inhibition of the peak control current during the27^(th) depolarization to +40 mV (in the 5 Hz train) is plotted as afunction of antagonist concentration. The concentrations of drugrequired to inhibit current by 50% (IC₅₀) are determined by fitting ofthe Hill equation to the concentration response data: % ofControl=100×(1+([Drug]/IC₅₀)^(p))⁻¹

For each cell four arithmetic metrics are obtained:

-   1) seal resistance-   2) baseline metric (the mean current at −70 mV from 5 to 45 ms    before the first depolarization to +40 mV)-   3) current run up metric (pre-compound mean current amplitude during    the 1^(st) depolarization to +40 mV minus the pre-compound mean    current amplitude during the 27^(th) depolarization to +40 mV)-   4) peak current (maximum current amplitude during the 27^(th)    depolarization to +40 mV during the 5 Hz train).

All metrics are obtained during both the pre- and post-compound additiontraces. Cells are eliminated from further analysis if:

-   1) seal resistance is <50 MΩ-   2) baseline metric is >±100 pA during the pre-compound-   3) current run up metric is >−0.2 nA-   4) pre-read peak metric is <400 pA.

The above-listed compounds provide ≧20% inhibition at a concentration of33 μM or less in the high throughput Kv1.5 planar patch clamp assaydescribed above.

Atomic Absorption Spectroscopy Protocol:

This assay identifies agents that specifically block the human Kv1.5 K+channel heterologously expressed in CHO cells as measured by Rb⁺ effluxusing Flame Atomic Absorption Spectroscopy (FAAS). The application ofFAAS for measuring ion channel activity was adapted from Terstappen etal, Anal. Biochem, 272:149-155, 1999.

CHO cells expressing human Kv1.5 are cultured as described above, thenharvested with trypsin-EDTA and washed with medium.

-   1. 40,000 cells per well are seeded in a 96-well cell culture plate    (assay plate) and the cells are allowed to grow for 48 hours at 37°    C.-   2. The medium is removed and 200 μl of Rb Load Buffer (Aurora    Biomed, Vancouver, BC) is added for 3 hours at 37° C. under 5% CO₂.-   3. The cells are washed 5 times with 200 μl Hank's Balanced Salt    Solution (HBSS) followed by the addition of 100 μl HBSS containing    test compound or 0.5% DMSO.-   4. After 10 min, 100 μl of HEPES-buffered saline containing 140 mM    KCl is added and plate is incubated at RT for 5 min. with gentle    shaking.-   5. Immediately thereafter, 150 μl of supernatant is transferred to a    fresh 96 well plate and the remaining supernatant aspirated.-   6. 120 μl of Cell Lysis Buffer (Aurora Biomed, Vancouver, BC) is    added to the assay plate and shaken for 10 min. prior to analysis.-   7. Rb content is measured in samples of supernatant (SUP) and lysate    (LYS) using an ICR-8000 automated AAS instrument (Aurora Biomed,    Vancouver, BC).    % FLUX=100%*(SUP/(LYS+SUP)). % INH=100%*(1−(A−B)/(C−B)), where A is    % FLUX in the presence of tested compound, B is % FLUX in the    presence of 10 mM    (6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)-N,N-dimethylmethanaminium    chloride, C is % FLUX in the presence of 0.25% DMSO.

The above-listed compounds provide ≧25% inhibition at a concentration of25 μM or less in the AAS assay described above.

The compounds of this invention can be administered for the treatment orprevention of afflictions, diseases and illnesses according to theinvention by any means that effects contact of the active ingredientcompound with the site of action in the body of a warm-blooded animal.For example, administration, can be oral, topical, includingtransdermal, ocular, buccal, intranasal, inhalation, intravaginal,rectal, intracisternal and parenteral. The term “parenteral” as usedherein refers to modes of administration which include subcutaneous,intravenous, intramuscular, intraarticular injection or infusion,intrasternal and intraperitoneal.

The compounds can be administered by any conventional means availablefor use in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination of therapeutic agents. They canbe administered alone, but are generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

For the purpose of this disclosure, a warm-blooded animal is a member ofthe animal kingdom possessed of a homeostatic mechanism and includesmammals and birds.

The dosage administered will be dependent on the age, health and weightof the recipient, the extent of disease, kind of concurrent treatment,if any, frequency of treatment and the nature of the effect desired.Usually, a daily dosage of active ingredient compound will be from about1-500 milligrams per day. Ordinarily, from 10 to 100 milligrams per dayin one or more applications is effective to obtain desired results.These dosages are the effective amounts for the treatment and preventionof afflictions, diseases and illnesses described above, e.g., cardiacarrhythmias such as atrial fibrillation, atrial flutter, atrialarrhythmia, and supraventricular tachycardia, thromboembolic events suchas stroke and congestive heart failure, and immunodepression.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, troches, dragées, granules and powders, or inliquid dosage forms, such as elixirs, syrups, emulsions, dispersions,and suspensions. The active ingredient can also be administeredparenterally, in sterile liquid dosage forms, such as dispersions,suspensions or solutions. Other dosages forms that can also be used toadminister the active ingredient as an ointment, cream, drops,transdermal patch or powder for topical administration, as an ophthalmicsolution or suspension formation, i.e., eye drops, for ocularadministration, as an aerosol spray or powder composition for inhalationor intranasal administration, or as a cream, ointment, spray orsuppository for rectal or vaginal administration.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene gycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propylparaben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, A. Osol, a standard reference text in thisfield.

For administration by inhalation, the compounds of the present inventionmay be conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or nebulisers. The compounds mayalso be delivered as powders which may be formulated and the powdercomposition may be inhaled with the aid of an insufflation powderinhaler device. The preferred delivery system for inhalation is ametered dose inhalation (MDI) aerosol, which may be formulated as asuspension or solution of a compound of Formula I in suitablepropellants, such as fluorocarbons or hydrocarbons.

For ocular administration, an ophthalmic preparation may be formulatedwith an appropriate weight percent solution or suspension of thecompounds of Formula I in an appropriate ophthalmic vehicle, such thatthe compound is maintained in contact with the ocular surface for asufficient time period to allow the compound to penetrate the cornealand internal regions of the eye.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention include, but are not limited to, hard and soft gelatincapsules, tablets, parenteral injectables, and oral suspensions.

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol. The solution is made to volume with water forinjection and sterilized.

An aqueous suspension is prepared for oral administration so that each 5milliliters contain 100 milligrams of finely divided active ingredient,100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodiumbenzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 millilitersof vanillin.

The same dosage forms can generally be used when the compounds of thisinvention are administered stepwise or in conjunction with anothertherapeutic agent. When drugs are administered in physical combination,the dosage form and administration route should be selected depending onthe compatibility of the combined drugs. Thus the term coadministrationis understood to include the administration of the two agentsconcomitantly or sequentially, or alternatively as a fixed dosecombination of the two active components.

Compounds of the invention can be administered as the sole activeingredient or in combination with a second active ingredient, includingother antiarrhythmic agents having Kv1.5 blocking activities such asquinidine, propafenone, ambasilide, amiodarone, flecainide, sotalol,bretylium, dofetilide, almokalant, bepridil, clofilium, other compoundshaving Kv1.5 blocking activities such as clotrimazole, ketoconazole,bupivacaine, erythromycin, verapamil, nifedipine, zatebradine,bisindolylmaleimide, or other cardiovascular agents such as, but notlimited to, ACE inhibitors such as benazepril, captopril, enalapril,fosinopril, lisinopril, moexipril, perindopril erbumine, quinapril,ramipril, and trandolapril, angiotensin II antagonists such ascandesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan,and valsartan, cardiac glycosides such as digoxin, L-type calciumchannel blockers, T-type calcium channel blockers, selective andnonselective beta blockers, an immunosuppresant compound, endothelinantagonists, thrombin inhibitors, aspirin, nonselective NSAIDs otherthan aspirin such as naproxen, warfarin, factor Xa inhibitors, lowmolecular weight heparin, unfractionated heparin, clopidogrel,ticlopidine, IIb/IIIa receptor antagonists such as tirofiban, 5HTreceptor antagonists, integrin receptor antagonists, thromboxanereceptor antagonists, TAFI inhibitors and P2T receptor antagonists.Compounds of the invention can also be administered as the sole activeingredient or in combination with a pacemaker or defibrillator device.

1. A compound of the structure:

or a pharmaceutically acceptable salt, crystal form, or hydrate,wherein: A is a) an aryl ring, wherein any stable aryl ring atom isindependently unsubstituted or substituted with 1) halogen, 2) NO₂, 3)CN, 4) CR⁴⁶=C(R⁴⁷R⁴⁸)₂, 5) C≡CR⁴⁶, 6) (CR^(i)R^(j))_(r)OR⁴⁶, 7)(CR^(i)R^(j))_(r)N(R⁴⁶R⁴⁷), 8) (CR^(i)R^(j))_(r)C(O)R⁴⁶, 9)(CR^(i)R^(j))_(r)C(O)OR⁴⁶, 10) (CR^(i)R^(j))_(r)R⁴⁶, 11)(CR^(i)R^(j))_(r)S(O)₀₋₂R⁶¹, 12) (CR^(i)R^(j))_(r)S(O)₀₋₂N(R⁴⁶R⁴⁷), 13)OS(O)₀₋₂R⁶¹, 14) N(R⁴⁶)C(O)R⁴⁷, 15) N(R⁴⁶)S(O)₀₋₂R⁶¹, 16)(CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹, 17) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹OR⁴⁷, 18)(CR^(i)R^(j))_(r)N(R⁴⁶) (CR^(k)R^(l))_(s)C(O)N(R⁴⁷R⁴⁸), 19) N(R⁴⁶)(CR^(i)R^(j))_(r)R⁶¹, 20) N(R⁴⁶) (CR^(i)R^(j))_(r)N(R⁴⁷R⁴⁸), 21)(CR^(i)R^(j))_(r)C(O)N(R⁴⁷R⁴⁸), or 22) oxo, or b) a heteroaryl ringselected from the group consisting of a 5-membered unsaturatedmonocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected fromthe group consisting or N, O or S, a 6-membered unsaturated monocyclicring with 1, 2, 3 or 4 heteroatom ring atoms selected from the groupconsisting N, O and S, and a 9- or 10-membered unsaturated bicyclic ringwith 1, 2, 3 or 4 heteroatom ring atoms selected from the groupconsisting or N, O or S; wherein any stable S heteroaryl ring atom isunsubstituted or mono- or di-substituted with oxo, and any stable C or Nheteroaryl ring atom is independently unsubstituted or substitutedwith 1) halogen, 2) NO₂, 3) CN, 4) CR⁴⁶═C(R⁴⁷R⁴⁸)₂, 5) C≡CR⁴⁶, 6)(CR^(i)R^(j))_(r)OR⁴⁶, 7) (CR^(i)R^(j))_(r)N(R⁴⁶R⁴⁷), 8)(CR^(i)R^(j))_(r)C(O)R⁴⁶, 9) (CR^(i)R^(j))_(r)C(O)OR⁴⁶, 10)(CR^(i)R^(j))_(r)R⁴⁶, 11) (CR^(i)R^(j))_(r)S(O)₀₋₂R⁶¹, 12)(CR^(i)R^(j))_(r)S(O)₀₋₂N(R⁴⁶R⁴⁷), 13) OS(O)₀₋₂R⁶¹, 14) N(R⁴⁶)C(O)R⁴⁷,15) N(R⁴⁶)S(O)₀₋₂R⁶¹, 16) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹, 17)(CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹OR⁴⁷, 18) (CR^(i)R^(j))_(r)N(R⁴⁶)(CR^(k)R^(l))_(s)C(O)N(R⁴⁷R⁴⁸), 19) N(R⁴⁶) (CR^(i)R^(j))_(r)R⁶¹, 20)N(R⁴⁶) (CR^(i)R^(j))_(r)N(R⁴⁷R⁴⁸), 21) (CR^(i)R^(j))_(r)C(O)N(R⁴⁷R⁴⁸),or 22) oxo; R¹ and R⁵ together with the atoms to which they areattached, form a ring selected from the group of structures consistingof

where u is 0 or 1, R⁹⁹ is hydrogen or —OH, and X is O or

=NOH; R², R⁸, R⁹ and R¹⁰ are independently selected from: 1) hydrogen,2) halogen, 3) NO₂, 4) CN, 5) CR⁴³═C(R⁴⁴R⁴⁵), 6) C≡CR⁴³, 7)(CR^(e)R^(f))OR⁴³, 8) (CR^(e)R^(f))N(R⁴³R⁴⁴), 9) (CR^(e)R^(f))C(O)R⁴³,10) (CR^(e)R^(f))C(O)OR⁴³, 11) (CR^(e)R^(f))R⁴³, 12)(CR^(e)R^(f))PS(O)₀₋₂R⁶⁰, 13) (CR^(e)R^(f))PS(O)₀₋₂N(R⁴³R⁴⁴), 14)OS(O)₀₋₂R⁶⁰, 15) N(R⁴³)C(O)R⁴⁴, 16) N(R⁴³)S(O)₀₋₂R⁶⁰, 17)(CR^(e)R^(f))N(R⁴³)R⁶⁰, 18) (CR^(e)R^(f))N(R⁴³)R⁶⁰OR⁴⁴, 19)(CR^(e)R^(f))_(p)N(R⁴³) (CR^(g)R^(h))_(q)C(O)N(R⁴⁴R⁴⁵), 20) N(R⁴³)(CR^(e)R^(f))R⁶⁰, 21) N(R⁴³) (CR^(e)R^(f))N(R⁴⁴R⁴⁵), and 22)(CR^(e)R^(f))_(p)C(O)N(R⁴³R⁴⁴), or R² and R⁸ are independently asdefined above, and R⁹ and R¹⁰, together with the atoms to which they areattached, form the ring

where R^(m) is C₁₋₆alkyl; R^(a), R^(b), R^(c), R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j), R^(k), and R^(l) are independently selectedfrom the group consisting of: 1) hydrogen, 2) C₁-C₆ alkyl, 3) halogen,4) aryl, 5) R⁸⁰, 6) C₃-C₁₀ cycloalkyl, and 7) OR⁴, said alkyl, aryl, andcycloalkyl being unsubstituted, monosubstituted with R⁷, disubstitutedwith R⁷ and R¹⁵, trisubstituted with R⁷, R¹⁵ and R¹⁶, ortetrasubstituted with R⁷, R¹⁵, R¹⁶ and R¹⁷; R⁴, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴,R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², and R⁵³ and are independentlyselected from the group consisting of 1) hydrogen, 2) C₁-C₆ alkyl, 3)C₃-C₁₀ cycloalkyl, 4) aryl, 5) R⁸¹, 6) CF₃, 7) C₂-C₆ alkenyl, and 8)C₂-C₆ alkynyl, said alkyl, aryl, and cycloalkyl is unsubstituted,mono-substituted with R¹⁸, di-substituted with R¹⁸ and R¹⁹,tri-substituted with R¹⁸, R¹⁹ and R²⁰, or tetra-substituted with R¹⁸,R¹⁹, R²⁰ and R²¹; R⁶, R⁶⁰, R⁶¹, R⁶² and R⁶³ are independently selectedfrom the group consisting of 1) C₁-C₆ alkyl, 2) aryl, 3) R⁸³, and 4)C₃-C₁₀ cycloalkyl; said alkyl, aryl, and cycloalkyl is unsubstituted,mono-substituted with R²⁶, di-substituted with R²⁶ and R²⁷,tri-substituted with R²⁶, R²⁷ and R²⁸, or tetra-substituted with R²⁶,R²⁷, R²⁸ and R²⁹; R⁷, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴,R²⁵, R²⁶, R²⁷, R²⁸, and are independently selected from the groupconsisting of 1) C₁-C₆ alkyl, 2) halogen, 3) OR⁵¹, 4) CF₃, 5) aryl, 6)C₃-C₁₀ cycloalkyl, 7) R⁸⁴, 8) S(O)₀₋₂N(R⁵¹R⁵²), 9) C(O)OR⁵¹, — 10)C(O)R⁵¹, 11) CN, 12) C(O)N(R⁵¹R⁵²), 13) N(R⁵¹)C(O)R⁵², 14) S(O)₀₋₂R⁶³,15) NO₂, and 16) N(R⁵¹R⁵²); R⁸⁰, R⁸¹, R⁸², R⁸³ and R⁸⁴ are independentlyselected from a group of unsubstituted or substituted hetrocyclic ringsconsisting of a 4-6 membered unsaturated or saturated monocyclic ringwith 1, 2, 3 or 4 heteroatom ring atoms selected from the groupconsisting N, O and S, and a 9- or 10-membered unsaturated or saturatedbicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from thegroup consisting or N, O or S; and n, p, q, r, and s are independently1, 2, 3, 4, 5 or 6; provided that when R⁹ is OCH₃, R¹ is CH₃ and R⁵ isC(CH₃)₃, then A is substituted, when R⁹ is hydrogen, R¹ is CH₃, and R⁵is hydrogen, then A is substituted, when R⁹ is hydrogen, R¹ is CH₃, andR⁵ is C(CH₃)₃, then A is substituted, provided the subsistent is notCH₃, and when R⁹ is OCH₃, R¹ is CH₃, R⁵ is CH₃, then A is substitutedwherein the compound, or a pharmaceutically acceptable salt thereof, is11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione.2. A method of treating a condition in a mammal, the treatment of whichis effected or facilitated by K_(v)1.5 inhibition, which comprisesadministering a compound of claim 1 in an amount that is effective atinhibiting K_(v)1.5 wherein the condition is cardiac arrhythmia.
 3. Amethod of claim 2, wherein the cardiac arrhythmia is selected from thegroup consisting of atrial flutter, atrial arrhythmia andsupraventricular tachycardia.
 4. A method of claim 3, wherein thecardiac arrhythmia is atrial fibrillation.
 5. A method of treatingcardiac arrhythmia comprising administering a compound of claim 1 with acompound selected from one of the classes of compounds consisting ofantiarrhythmic agents having K_(v)1.5 blocking activities, ACEinhibitors, angiotensin II antagonists, cardiac glycosides, L-typecalcium channel blockers, T-type calcium channel blockers, selective andnonselective beta blockers, endothelin antagonists, thrombin inhibitors,aspirin, nonselective NSAIDs, warfarin, factor Xa inhibitors, lowmolecular weight heparin, unfractionated heparin, clopidogrel,ticlopidine, IIb/IIIa receptor antagonists, 5HT receptor antagonists,integrin receptor antagonists, thromboxane receptor antagonists, TAFIinhibitors and P2T receptor antagonists.
 6. A method for treatingtachycardia in a patient which comprises treating the patient with anantitachycardia device in combination with a compound of claim
 1. 7. Apharmaceutical formulation comprising a pharmaceutically acceptablecarrier and the compound claim 1 or a pharmaceutically acceptablecrystal form or hydrate thereof.
 8. A pharmaceutical composition made bycombining the compound of claim 1 and a pharmaceutically acceptablecarrier.